Abstract PS1-11-02: The ADELA study: a double-blind, placebo-controlled, randomized phase 3 trial of elacestrant + everolimus versus elacestrant + placebo in ER+/HER2- advanced breast cancer (ABC) patients with ESR1-mutated tumors progressing on endocrine therapy (ET) + CDK4/6i

Abstract Background: ET+CDK4/6i is the standard-of-care (SOC) in 1L ER+/HER2- ABC; however, tumors eventually develop resistance. Constitutive activation of the PI3K/AKT/mTOR pathway can contribute to endocrine resistance in breast cancer. ESR1 mutations are a common type of acquired resistance that emerges in 40-50% of patients in the metastatic setting after prolonged aromatase inhibitor exposure. There is an unmet need for novel therapeutic approaches to overcome resistance mechanisms and improve outcomes in patients with ER+/HER2- ABC with ESR1-mutated tumors progressing after ET+CDK4/6i. Elacestrant is a next-generation oral SERD that binds to ER-alpha, inducing its degradation. In the EMERALD study, single-agent elacestrant improved PFS vs SOC ET in patients with ESR1-mutated tumors (HR 0.55; 95% CI 0.39-0.77; P=0.0005) [Bidard 2022]. Differences were notable among patients who received prior ET+CDK4/6i ≥12 months; median PFS with elacestrant was 8.6 vs 1.9 months with SOC ET (HR 0.41; 95% CI 0.26-0.63) [Bardia 2024]. The crosstalk between the ER and PI3K/AKT/mTOR pathways provides a rationale for evaluating elacestrant+everolimus (a mTORC1 inhibitor). In the ELEVATE phase 1b trial (NCT05563220), the combination of elacestrant and everolimus demonstrated a median PFS of 8.3 months (95% CI, 3.9 to NR) in all patients (N=23) with ER+/HER2- ABC who progressed after ET+CDK4/6i, regardless of ESR1-mutation status (Rugo, ASCO 2025); elacestant 345 mg + everolimus 7.5 mg was identified as the RP2D [Rugo ESMO 2024]. Safety was consistent with the known profile of everolimus+SOC ET. The ADELA study compares elacestrant+everolimus vs elacestrant+placebo in ER+/HER2- ABC patients with ESR1-mutated tumors progressing on ET+CDK4/6i. Design and Methods: ADELA (NCT06382948) is an international, multicenter, double-blind, placebo-controlled phase 3 trial. Eligible patients are adults (≥18 years) with ER+/HER2- ABC and centrally confirmed ESR1 mutations, previously treated with 1-2 lines of ET for ABC, and evidence of disease progression on prior ET+CDK4/6i for ABC after ≥6 months. Patients receiving CDK4/6i-based adjuvant therapy are eligible provided that disease progression is confirmed after ≥12 months of treatment but